Liver function testing apparatus and method

ABSTRACT

In a liver function testing apparatus, light sources (11, 12) expose vital tissue (15) to a first light of a wavelength absorbed by specific dye dosed into blood of the vital tissue, whereby the dye is to be taken in and removed by a liver and a second light of a wavelength not absorbed by the dye. Optical pulses obtained from the vital tissue are received by a light receiving element (13) providing an output signal which is sampled by an A-D converter (30) for converting the output signal into digital sampling signals. Variable components in the blood represented by the sampling signals are determined as coefficients of linear functions, to perform a biocalibration. A value correlated with a specific dye concentration in the blood is processed on the basis of the digital sampling signals during a prescribed period after injection of a defined dose of the specific dye and on the basis of the determined coefficients, so that a coefficient of a simulation function which is a function of time is obtained by using the method of least squares. Additionally a blood plasma disappearance rate and a retention rate are obtained on the basis of the coefficient.

TECHNICAL FIELD

The present invention relates to a liver function testing apparatus andto a method for testing the function of a liver. More specifically, itrelates to a liver function testing apparatus for automaticallyperforming measurements for testing/diagnosing a liver function byinjecting a specific color dye, which is selectively taken in andremoved only by the liver, into the blood and measuring a blood plasmadisappearance rate and a retention rate thereof.

BACKGROUND INFORMATION

In general, the blood plasma disappearance rate and the retention ratehave been measured by a method of blood collection through use ofindocyanine green (hereinafter referred to as ICG) serving as a specificdye. According to this method, an intravenous injection of ICG is givento a testee and a blood sample is taken three times after lapses offive, ten and 15 minutes from the injection. The blood serum isseparated upon coagulation of a blood clot so that an absorbance at awavelength of 805 nm is measured through a spectrophotometer to obtainICG concentration values in the blood serum after the lapses of five,ten and 15 minutes relative to a previously obtained calibration curveshowing the ICG concentration in blood vs. absorbance thereby tocalculate the blood plasma disappearance rate and the retention rate. Inrecent years, a method of changing the quantity of the ICG injection hasbeen used to measure the blood plasma disappearance rate several timesthereby to obtain an index expressing a quantity of a hepatic cellfunction R_(MAX) (removed maximal).

Japanese Patent Publication Gazette No. 58649/1985 has already proposeda method of measuring the blood plasma disappearance rate and theretention rate without performing blood collections. According to thatmethod, light is applied through the body surface of an organism, whichin turn transmits light of a wavelength having a high ICG absorptionsensitivity and light of a wavelength having substantially no ICGabsorption sensitivity. The respective quantities of transmitted lightare measured to obtain the blood plasma disappearance rate and theretention rate of the light quantities as a function of time (dyedisappearance curve).

In the aforementioned first method requiring the taking of bloodsamples, it is necessary to correctly measure the blood collection timeafter the injection of the dye. However, the time has not beenaccurately measured in an actual test, and the operation for suchmeasurement has been complicated. Further, the testee has been subjectto substantial mental and physical burdens caused by the repeated takingof blood samples. In addition, the index R_(MAX) method for measuringthe blood plasma disappearance rate several times by changing thequantity of the ICG injection requires taking blood samples more thanten times, whereby the burdens on the testee are further increased.

According to the second measuring method without blood collection asdisclosed in Japanese Patent Publication No. 58649/1985, the output of asensor actually attached to an organism fluctuates under the influenceof such factors as a blood flow disturbance caused by compressionapplied to a blood vessel, vibration of the organism being the object ofmeasurement, pulsation in the organism, change of the blood volume inthe vital tissue (the blood volume in each part in the vital tissue ischanged by merely vertically moving an arm) etc. As a result correct dyedisappearance curve cannot be obtained.

SUMMARY OF THE INVENTION

Accordingly, a principal object of the present invention is to provide aliver function testing apparatus and method which remains uninfluencedby such factors as blood flow disturbance, vibration of an organism,pulsation in the organism and change of the blood volume in the vitaltissue, to enable correct measurements.

The present invention provides an apparatus for testing the function ofa liver. The apparatus comprises light source means for exposing vitaltissue to first light of a wavelength absorbed by specific dye which isdosed into blood of the vital tissue to be taken in and removed by theliver and second light of a wavelength not absorbed by the dye,photoelectric conversion means for outputting first and secondphotoelectric conversion signals corresponding to the first light andthe second light applied to the vital tissue from the light source meansand obtained from the vital tissue, sampling means for sampling thephotoelectric conversion signals, decision means for deciding thecoefficient of a linear regression expression between the first andsecond photoelectric conversion signals on the basis of variablecomponents in the blood included in the sampled first and secondphotoelectric conversion signals and arithmetic means for operating avalue correlated with specific dye concentration in the blood on thebasis of a sampling signal during a prescribed period after a lapse of apredetermined time from an injection of the specific dye and the decidedcoefficient of the regression line expression.

In a preferred embodiment of such a liver function testing apparatus, acoefficient of a simulation function in the form of a function of timeis obtained by using the method of least squares on the basis of theprocessed values correlated with the specific dye concentration.

In a further preferred embodiment of the present invention, a bloodplasma disappearance rate of the specific dye is found on the basis ofthe obtained coefficient of the simulation function.

In yet another preferred embodiment of the present invention, aretention rate of the specific dye in a prescribed period is found onthe basis of the obtained coefficient of the simulation function.

In a further embodiment of the present invention, an index expressing aquantity hepatic cell function R_(MAX) is found on the basis of theobtained coefficient of the simulation function.

Thus, according to the present invention, a first light of a wavelengthabsorbed by a specific dye dosed into the blood of vital tissue, saiddye to be taken in by and removed by the liver and a second light of awavelength not absorbed by the dye, are applied to the vital tissue andfirst and second photoelectric conversion signals corresponding to thefirst light and to the second light are obtained from the vital tissueby sample. A coefficient of a regression line expression or relationshipbetween the first and second photoelectric conversion signals, isdetermined on the basis of variable components in the blood asrepresented by the sampled first and second photoelectric conversionsignals to perform a biocalibration. Thus, a value correlated with aspecific dye concentration in the blood on the basis of sampling signalsobtained during a prescribed period of time following an injection ofthe specific dye and the decided coefficient of the regression lineexpression are availabe for processing to obtain liver function testingresults. Factors such as a blood flow disturbance, vibration andpulsation of an organism etc. when a sensor is attached to an organismcan be removed by biocalibration, to process or calculate the valuecorrelated with the specific dye concentration. Further, a correct timemanagement of a disappearance curve of the specific dye has becomepossible, for obtaining correct data of the blood plasma disappearancerate, the retention rate, an index expressing the total amount of thehepatic cell function, etc. The present more correct data need not bebased on several different blood samples as in conventional bloodcorrection method. Rather, the present test results are based on alarger number of data of the disappearance curve, whereby thereliability of the results is improved.

These and other objects, features, aspects and advantages of the presentinvention will become more apparent from the following detaileddescription of the invention when taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 4 are diagrams for illustrating the principle of the presentinvention;

FIG. 5 is a schematic block diagram showing the structure of anembodiment of the present invention;

FIG. 6 illustrates the timing for detecting quantities of light ofwavelengths λ₁ and λ₂ after passage through a prescribed optical path ina tested object;

FIG. 7 illustrates data stored in a RAM as shown in FIG. 1;

FIGS. 8A to 8D are flow charts for concretely illustrating the operationof the embodiment of FIG. 5, in which FIG. 8A shows a data samplingsubroutine, FIG. 8B shows a biocalibration mode, FIG. 8C shows aninitialization mode and FIG. 8D shows a measurement mode;

FIGS. 9 to 12 are illustrative of exemplary displays on a display deviceshown in FIG. 5;

FIG. 13 shows an example of a disappearance curve of a specific dye asmeasured in accordance with the present invention;

FIG. 14 shows the specific dye concentration Cg as a function of time asmeasured according to the invention for parameters k=0.125 (blood plasmadisappearance rate) and R=13% (15 minute retention rate).

FIG. 15 illustrates light quantity data L₁ and L₂ as a function of time;

FIGS. 16 to 19 are diagrams for illustrating effects obtained bypracticing the present invention;

FIG. 20 illustrates data stored in a RAM employed in another embodimentof the present invention;

FIGS. 21A and 21B are flow charts for illustrating the operation of ameasurement mode in another embodiment of the present invention; and

FIGS. 22 to 24 are diagrams for illustrating operation of anotherembodiment of the present invention.

DETAILED DESCRIPTION OF PREFERRED EXAMPLE EMBODIMENTS AND OF THE BESTMODE OF THE INVENTION

Before explaining the embodiments of the present invention, theprinciple of the biocalibration employed in practicing the presentinvention will first be described with reference to FIGS. 1 to 4.

It is assumed that symbols I₁ and I₂ indicate quantities of light havinga wavelength λ₁ which is largely absorbed by a specific dye and light ofa wavelength λ₂ which is not absorbed by the specific dye incident uponvital tissue 15 to be tested. The symbols L₁ and L₂ indicate lightquantities after passage through a prescribed optical path in the vitaltissue 15 such as a patient's fingertip. The relationships between theincident light quantities I₁ and I₂ and the passing light quantities L₁and L₂ after an injection of the specific dye, are as follows:

    log I.sub.1 /L.sub.1 =kg.sub.1.Cg.Vb+f.sub.1 (Cb, Vb)+γt.sub.1 (1)

    log I.sub.2 /L.sub.2 =f.sub.2 (Cb, Vb)+γt.sub.2      (2)

Respective coefficients and variables are shown in FIG. 1. Symbols f₁and f₂ represent functions which are determined by blood characteristicsat the wavelengths λ₁ and λ₂.

On the other hand, the relationships between the incident lightquantities I₁ and I₂ and the passing light quantities L₁ and L₂ beforeinjection of the specific dye are as follows:

    log I.sub.1 /L.sub.1 =f.sub.1 (Cb, Vb)+γt.sub.1      (3)

    log I.sub.2 /I.sub.2 =f.sub.2 (Cb, Vb)+γt.sub.2      (4)

The relationships between the passing light quantities L₁ and L₂ priorto an actual injection of the specific dye, is measured as shown FIG. 2and is a linear characteristic as shown in FIG. 3. These data areobtained by attaching a sensor to an organism and fluctuating the bloodvolume in the organism. It has been confirmed that such linearity has areproducibility without any individual differences.

Then, the expressions (3) and (4) would appear as follows:

    log L.sub.1 =A log L.sub.2 +B                              (5)

That is, the same can be expressed as follows, by using the expressions(3) and (4):

    log I.sub.1 -{f.sub.1 (Cb, Vb)+γt.sub.1 }=A[log I.sub.2 -{f.sub.2 (Cb, Vb)+γt.sub.2 }]+B                              (6)

where Cb represents the blood concentration in a sample and Vbrepresents the blood volume of the sample.

A function C obtained by multiplying the concentration of the specificdye by the blood volume in the sample and the absorption coefficient ofthe specific dye by using the expressions (1) and (2) after injection ofthe specific dye, can be expressed as follows:

    C=log L.sub.1 -[A log L.sub.2 +B]                          (7)

The function C of the expression (7) is found as follows:

    C=log I.sub.1 -kg.Cg.Vb-f.sub.1 (Cb, Vb)+γt.sub.1 -A[log I.sub.2 -{f.sub.2 (Cb, Vb)+γt.sub.2 }]-B                    (8)

Through the expression (6), we have:

    C=-kg.Cg.Vb                                                (9)

Hence, it is understood that a signal of the function C can be obtainedby using FIG. 3 as a biocalibration curve.

As to the function C, however, although the coefficient kg is constant,it can be considered that the blood volume Vb in each part changes fromtime to time, and hence, if the blood volume Vb in a prescribed samplecreated by the sensor once it is attached, is changed, the amount of thespecific dye is also changed in proportion thereto, however the dyeconcentration remains unchanged. This is typically shown in FIG. 4.

Referring to FIG. 4, it is assumed that DE represents the value of thefunction C after a lapse of t₁ minutes. The blood contained in theprescribed sample obtained after a lapse of t₁ +Δt minutes is changed involume, whereby the observation point is changed from E to E'. Assumingthat Δt is sufficiently less than one minute, the specific dyeconcentration in the blood after the lapse of t₁ minutes may beconsidered identical to that after the lapse of t₁ +Δt minutes. However,as to the function C, the change is from C=DE to C'=D'E'. C≠C', andhence some correction must be made. Hence, by normalizing DE and D'E' atthe point L₁₀, an apparent fluctuation of the dye concentration due tothe fluctuation of the blood volume can be corrected. When the specificdye is injected, a signal of only log L₁ changes to a point E, forexample. At this time, DE becomes the function C as shown in theexpression (9 ). The blood volume Vb in the expression (9) can beinterpreted as being denoted by CD, and hence, normalizing the Ycoordinate of a point A as L₁₀, the same is expressed as follows:##EQU1##

Hence, a signal Cg corresponding to the specific dye concentration canbe found by the expressions (7) and (10) as follows: ##EQU2##

Using the method of least squares, the function Cg of a simulation curverepresenting a time change of the aforementioned result Cg as calculatedis expressed as follows:

    Cg=Ae.sup.Bt                                               (12)

where t represents the elapsed time after injection of the specific dyeand symbols A and B represent constants.

The constants A and B are found by the above expression (12). The bloodplasma disappearance rate k and the T-minute retention rate R % areexpressed as follows:

    k=-B                                                       (13)

    R%=e.sup.BT                                                (14)

where T represents the elapsed time after injection characteristicallyexpressing the intake of the specific dye into the liver.

An embodiment of the present invention employing the aforementionedbiocalibration, will now be described with reference to FIG. 5 showing aschematic block diagram.

The liver function testing apparatus of FIG. 5 comprises a sensor part10 and a measured signal processing part 20. The sensor part 10 includesa first light source 11, a second light source 12, a light receivingelement 13 and a preamplifier 14. The first light source 11 and thesecond light source 12 generate optical pulses of a wavelength λ₁ havinga large absorbance to a specific dye and optical pulses of a wavelengthλ₂ having no absorbance, respectively. The light receiving element 13receives light applied to vital tissue 15 from the light sources 11 and12 to pass through a prescribed optical path. The light sources 11 and12 are energized by the measurement processing part 20 to alternatelyemit light by pulse operation, respectively.

The measurement processing part 20 includes a CPU 34 which operates as aarithmetic means. The CPU 34 supplies a start signal to an oscillationcircuit 24 and a timing circuit 23 through an I/O port 32. Theoscillation circuit 24 regularly oscillates to produce a prescribedclock signal. This clock signal and the aforementioned start signal areutilized to supply constant currents i₁ and i₂ to the first light source11 and to the second light source 12 from a constant current circuit 21through the timing circuit 23 and a decoder 22 at timings TM₁ ' and TM₁" in FIG. 6.

The light emitted by the first light source 11 and the light emitted bythe second light source 12 pass through the prescribed optical path inthe vital tissue 15, to be incident upon the light receiving element 13.A current generated by the light receiving element 13 is supplied to thepreamplifier 14 for a current-to-voltage conversion and amplificationfor further processing in the measurement processing part 20. The outputof the preamplifier 14 is amplified to a level within a prescribed rangeby an amplifier 16 provided in the measurement processing part 20,whereby an output such as V_(PD) in FIG. 6 is obtained. A sample andhold circuit 28 samples and holds the output from the amplifier 16 onthe basis of a timing signal TM₂ ', shown in FIG. 6, generated by thetiming circuit 23 and a decoder 25.

The signal thus sampled and held is selected by a multiplexer 29 andconverted into a digital signal by an A-D converter 30, to bedata-latched by a data latch circuit 31. At this time, the multiplexer29, the A-D converter 30 and the data latch 31 are synchronized by thetiming circuit 23 and the decoder 26.

The latched data are timed by a decoder 27 through a select signaloutputted from the CPU 34 through the I/O port 32, to be stored in a RAM35 as digital signal L₁ and L₂. The I/O port 32 is connected to a buzzer33, which informs an operator regarding the timing for injecting thespecific dye. Further, the CPU 34 is connected with the RAM 35, a ROM36, a display 37 and an operation part 28. The RAM 35 is adapted tostore data as shown in FIG. 7 as will be described, below and the ROM 36stores programs based on flow charts as shown in FIGS. 8A to 8D to bedescribed below. The display 37 displays data as shown in FIGS. 9 to 12,as hereinafter described. A printer 38 prints the result of a liverfunction test.

The function part 39 includes an alarm LED 40, a calibration key 41, astart key 42 and a print key 43. The alarm LED 40 causes an alarm whenthe reliability of the test result is small and the calibration key 41is used to set a biocalibration mode, while the start key 42 is used tostart a measurement mode and the print key 43 is used to cause aprintout of the test result.

In the aforementioned exemplary structure as shown in FIG. 5, the lightemitted by the first and second light sources 11 and 12 and caused topass through the prescribed optical path in the vital tissue 15 isreceived by a single light receiving element 13. However, the presentmethod is not restricted to the use of a single light sensor but lightreceiving elements may be provided in correspondence to the first andsecond light sources 11 and 12, respectively, for sampling outputs ofthe respective light receiving elements, thereby to read the respectivesampling outputs by the CPU 34 in a time-sharing manner. Alternatively,a single light source commonly emitting light having a wavelength λ₁absorbed by specific dye and light having a wavelength λ₂ not absorbedby the same may be provided as light source means, with provision of twofilters for individually transmitting the light of the respectivewavelengths and light receiving elements corresponding to the respectivefilters would be used.

With reference to FIGS. 5, 8A to 8D and 14, an actual operation sequenceof an embodiment of the present invention will now be described.

The operation of the inventive apparatus includes a data sampling mode,a biocalibration mode, an initialization mode and a measurement mode,and FIGS. 8A, 8B, 8C and 8D show operation flow charts for these modes,respectively.

First, it is pointed out that the data sampling mode as shown in FIG. 8Ais executed as subroutines in the calibration mode and the measurementmode as hereinafter described. Steps (abbreviated as SP in the figures)SP11 to SP16 are adapted to sample quantities of light of a pair ofwavelengths λ₁ and λ₂ after passage through a measured object and storethe same in the RAM 35. Namely, the CPU 34 outputs the start signal froma line as shown in FIG. 5 through the I/O port 32 at the step SP11. Thevalues L₁ and L₂ are data-latched by the start signal, as hereinabovedescribed. The CPU 34 waits until the data are latched at the step SP12.

Then, at the step SP13, the CPU 34 outputs the select signal to a selectline as shown in FIG. 5 through the I/O port 32, to read the data of L₁through the I/O port 32 at the step SP14, thereby to store the same in astorage area 8a1 of the RAM 35 as shown in FIG. 7.

Similarly, the CPU 34 stores the data of L₂ in a storage area 8a2 of theRAM 35 at the steps SP15 and SP16.

Upon completion of the aforementioned operation or processing at thestep SP16, the CPU 34 returns to the original step. This will bedescribed with reference to FIG. 8B showing the biocalibration mode andFIG. 8D showing the measurement mode.

FIG. 8B shows the operation flow chart of the biocalibration mode, whichis started upon power supply to the apparatus or upon completion of theoperation of the measurement mode as shown in FIG. 8D, as hereinafterdescribed. At a step SP21, the CPU 34 causes the biocalibration mode toappear on the display 37 and indicates that the sensor part 10 should beattached to a patient as shown in FIG. 9, for example. In accordancewith this indication, an operator attaches the sensor part 10 to thevital tissue 15.

Thereafter the CPU 34 waits until the calibration key 41 is operated ata step SP22. When the calibration key 41 has been operated, the CPU 34advances to a step SP23, to execute the data sampling subroutine asshown in FIG. 8A, as described above.

Then, the CPU 34 controls the constant current circuit 21 as shown inFIG. 5 so that the data L₁ and L₂ read at the step SP23 are withinranges of the light quantity data L_(MAX) and L_(MIN) stored in storageareas 8b1 and 8b2 of the RAM 35. The CPU 34 then stores current setvalues i₁, i₂ in storage areas 8c1 and 8c2 in the RAM 35. Thereafter thecurrents i₁, i₂ regularly flow to the light sources 11 and 12. Startingthe operation for causing the aforementioned currents will be describedin further detail with reference to FIG. 8C.

Then, the CPU 34 sounds the buzzer at a step SP25, to inform that powersetting is completed. Subsequent steps SP26 to SP29 are shown in theflow chart for performing the aforementioned biocalibration. Morespecifically, the CPU 34 samples the values of L₁ and L₂ n timesrespectively at the steps SP26 and SP27, to cause CL₁ (1) to CL₁ (n) tobe stored in storage areas 8d1 to 8dn and CL₂ (1) to CL₂ (n) stored instorage areas 8e1 to 8en. At the subsequent step SP28, the CPU 34performs a regression line analysis with respect to log CL₁ (I) and logCL₂ (I) (I=1 to n), in accordance with the following operationexpression:

    log Cl.sub.1 (I)=A log CL.sub.2 (I)+B

The CPU 34 finds the values A and B in the above operation expression, acorrelation coefficient r₁ and the maximum value of CL₁ (I), (I=1 to n)as CL₁₀, to store the same in storage areas 8f1, 8f2, 8f3 and 8f4 in theRAM 35, respectively.

Then, at the step SP29, the CPU 34 determines whether or not thecorrelation coefficient r₁ is at least 0.998 in order to verify thereliability of the biocalibration, and advances to a step SP30 if thesame is less than 0.998 to light the alarm LED 40, and returns to thestep SP22 to again perform biocalibration. On the other hand, if adetermination is made that the correlation coefficient r₁ is at least0.998, the CPU 34 advances to the measurement mode as shown in FIG. 8D.The reference value 0.998 of the correlation coefficient r₁ hereinemployed is a mere example, which is determined based on the performanceof the entire apparatus. During the data sampling by n times at the stepSP26, the testee raises and brings down his hand and compresses the sameby the sensor, in order to change the blood volume in the hand.

With reference to FIG. 8C, the aforementioned initializing operation atthe step SP24 as shown in FIG. 8B will now be described in more detail.

The light quantity data L₁ and L₂ of the light of the wavelengths λ₁ andλ₂ are stored in the storage areas 8a1 and 8a2 of the RAM 35. At a stepSP241, the CPU 34 stores the values of L₁ and L₂ in storage area 8h1 and8h2 in the RAM 35 as L0λ₁ and L0λ₂, respectively. Then the CPU 34executes steps SP242 to SP249, to adjust the set values of the currentsflowing from the constant current circuit 21 so that L0λ₁ and L0λ₂ areset between the light quantity data L_(MAX) and L_(MIN) (L_(MAX)>L_(MIN)) stored in the storage areas 8b1 and 8b2 of the RAM 35.

More specifically, if L0λ₁ is greater than L_(MAX) at the step SP242,the CPU 34 advances to the step SP243 to set the current set value i₁ ata small value to again execute the steps SP23 and SP241, and adetermination is again made as to whether or not L0λ'₁ is greater thanL_(MAX) at the step SP242. If L0λ₁ is less than L_(MAX), the CPU 34advances to the step SP244 to determine whether or not L0λ₁ is less thanL_(MIN). If L0λ₁ is less than L_(MIN), the CPU 34 increases the value ofthe current set value i₁ at the step SP245, to return to theaforementioned step SP23. This operation is repeated to set the currentvalue i₁ so that L0λ₁ is between L_(MAX) and L_(MIN).

Then, at the steps SP246 to SP249, the current value i₂ is set so thatL0λ₂ is between L_(MAX) and L_(MIN), similarly to the steps SP242 toSP245. Thus, the current values i₁ and i₂ finally set at the steps SP23to SP249, are stored in the storage areas 8c1 and 8c2 of the RAM 35.

The measurement mode will now be described with reference to FIG. 8D. Ata step SP41, the CPU 34 alerts the operator by an indication on thedisplay 37, to inject the specific dye into the patient, for example, anICG injection as shown in FIG. 10. The operator prepares the injectionof the specific dye and at step SP42, the CPU 34 waits until the startkey 42 is operated. Upon a determination that the start key 42 has beenoperated, the CPU 34 displays a timing for the injecting of the specificdye at a step SP43, while sounding the buzzer 33. This operation isdisplayed as 1→2→3→4→5 as shown in FIG. 11, for example, so that themeasurer injects the specific dye upon display of "5". The CPU 34generates a first sound from the buzzer 33 with the displays of "1","2", "3" and "4", while generating a different sound from the buzzer 33upon display of "5".

Upon generation of the sound and the display, the measurer injects thespecific dye. The CPU 34 sets "0" as the initial value of a timer at astep SP44. Then, at a step SP45, the CPU 34 executes a data samplingprogram, which is the subroutine as described above with reference toFIG. 8A. Then, the sampling data are stored in the storage areas 8a1 to8a2 of the RAM 35 as L₁ to L₂, respectively. At a step SP46, the CPU 34performs an operation based on the following operation expression byusing the coefficients A, B, and L₁₀ stored in the storage areas 8f1,8f2 and 8f4 of the RAM 35 in the biocalibration mode as described abovewith reference to FIG. 8B, to store Cg(I) in a storage area 8g1 of theRAM 35: ##EQU3##

The value of Cg(I) is displayed on the display 37 at the step SP46 in amode as shown in FIG. 12, for example. Referring to FIG. 12, theabscissa indicates the elapsed time from the injection of the specificdye and the ordinate indicates the value of Cg(I). Assuming that mrepresents the sampling number of a disappearance curve of the specificdye, symbol I indicates integers 1 to m, and assuming that T_(s)represents a measuring time of the disappearance curve, a singlesampling time is ITM=T_(s) /(m-1). The same coincides with the injectiontime of the specific dye in the case of I=1. At a step SP47, the CPU 34waits during this sampling time ITM.

Upon a lapse of this standby time, the CPU 34 judges whether or not i isgreater than m at a step SP48. The CPU 34 advances to a step SP49 if iis greater than m, while the same again returns to the step SP45 torepeat sampling if i is less than the m. The data Cg(I) stored in thestorage areas 8g1 to 8gm of the RAM 35 draw a disappearance curve of thespecific dye as shown in FIG. 13, for example, and the leading edgethereof is detected so that data preceding thereto are subtracted asbaselines from the respective values of Cg(I), to be again stored in thestorage areas 8g1 to 8gm. L₁ to L₂ at the step SP45 may be averagevalues of k times, in order to improve the accuracy of the measurement.

Then, at a step SP51, the CPU 34 finds the constants A and B by usingthe method of least squares in a simulation curve of:

    Cg(I)=Ae.sup.Bt wherein

    I=T.sub.s /(m=1)(min.)

with respect to data between times T₁ to T₂ (0<T₁ <T₂ <T_(s)) within thedata Cg(I) stored in the storage areas 8g1 to 8gm.

Then, the CPU 34 performs an operation to evaluate the blood plasmadisappearance rate k=-B and the T-minute retention rate R %=e^(BT) at astep SP52. The values k and R % thus evaluated are stored in storageareas 8j1 and 8j2 of the RAM 35, respectively. At this time, the CPU 34determines a correlation coefficient r₂ by the method of least squaresand stores the correlation coefficient r₂ in a storage area 8j3 of theRAM 35. The CPU 34 further generates an end sound from the buzzer 33.

Further, the CPU 34 causes the values k and R % to appear on the display34 in a mode as shown in FIG. 12, for example. Then, at a step SP53, theCPU 34 determines whether or not the correlation coefficient r₂ is lessthan 0.95, for example. This determination is made to check the degreeof correlation since the correlation is improved as the correlationcoefficient r₂ approaches -1. The value -0.95 is provisionally selectedbetween zero and -1, and the reliability of the apparatus is improved asthe value comes closer to -1.

If the correlation coefficient r₂ is greater than 0.95, for example, theCPU 34 determines that the reliability is insufficient and this isindicated by switching on the alarm LED 40 at the step SP54. On theother hand, if the correlation coefficient r₂ is less than -0.95, forexample, at the step SP53, the CPU 34 advances to a step SP55 withoutflashing the alarm LED 44, since the measurement is reliable. At thestep SP55, the CPU 34 determines whether or not the print key 43 isoperated, to cause the printer 38 to print the values k and R % if thedetermination is YES.

If necessary, the CPU 34 also causes the printing of dye disappearancecurves of Cg(I) stored in the storage areas 8g1 to 8gn of the RAM 35 andit may cause an advance to the biocalibration mode as shown in FIG. 8B.When a determination is made that the print key 43 has not been operatedat the step SP55, the CPU 34 advances to the calibration mode.

FIG. 14 shows the result of a measurement experiment in the liverfunction testing apparatus as shown in FIG. 5. The sensor part 10 wasattached on a left fingertip of a male patient having hepatic disease(age: 60, weight: 48 Kg). An aqueous containing 24 mg of ICG (0.5 mg perKg) was intravenously injected into the vein at the vein of his rightelbow. FIG. 15 shows the time change of L₁, L₂ where a light emittingdiode emitting light at a wavelength λ₁ =810 nm is used as the firstlight source 11 and a light emitting diode emitting light at awavelength λ₂ =940 nm is used as the second light source 12.

The value k calculated on the basis of the ICG disappearance curve was0.125 as shown in FIG. 14 and the value R % was 13%, while the value kmeasured by the conventional blood collection method was 0.124 and thevalue R % was 12.8%, showing a substantial coincidence. FIG. 15 alsoshows raw data of L₁ and L₂. It is clearly understood from FIG. 14 thatthe blood volume in the organism fluctuated.

FIGS. 16 to 19 show results of experiments for illustrating the effectsattained by the present invention.

FIG. 16 shows time changes for 15 minutes in intensity levels of thefirst light and the second light passing through the vital tissue 15from the light sources 11 and 12 while bringing the vital tissue 15 in arest state. Merely finding difference (L₁ -L₂) between the first lightand the second light, the base line largely fluctuated as characteristica in FIG. 17. When the fluctuation of the blood volume is corrected bythe biocalibration according to the present invention, the base line issubstantially stable as shown by characteristic b in FIG. 17.

FIG. 18 shows time changes for 15 minutes in intensity levels of thefirst light and the second light passing through the vital tissue 15from the light sources 11 and 12 when the testee's body is moved tocause a blood volume fluctuation. An evaluation of the differencebetween the first light and the second light with such a largefluctuation, show that the base line fluctuates substantially as shownby characteristic a in FIG. 19. When the fluctuation of the blood volumeis corrected by the biocalibration according to the present invention,the base line is substantially stabilized as shown by characteristic bin FIG. 19.

In the aforementioned embodiment, the present invention is applied tothe case of evaluating the coefficient of the simulation function byusing the method of least squares on the basis of the value correlatedwith the specific dye concentration in the blood for evaluating theblood plasma disappearance rate k and the retention rate R %. However,the present invention is not restricted to this but further applicableto the case of obtaining index R_(MAX) on the basis of theaforementioned coefficient as obtained. Description is now made on suchan embodiment with reference to FIG. 20 illustrating data stored in aRAM provided in an apparatus for measuring the index R_(MAX).

The apparatus for measuring the index R_(MAX) is identical in structureto that shown in FIG. 5, but the RAM 35 is provided with storage areas8k1 to 8k6 and 8l1 and 8l2 as shown in FIG. 20, in place of the storageareas 8j1 to 8j3 as shown in FIG. 7.

A data sampling mode in measuring the index R_(MAX) is identical to thatshown in FIG. 8A and a biocalibration mode is identical to that shown inFIG. 8B. The initializing operation or processing is identical to thatshown in FIG. 8C. Within the operation or processing of the measurementmode as shown in FIGS. 21A and 21B, steps SP41 to SP51 and SP53 to SP56are identical to those shown in FIG. 8D, and hence will not be describedagain.

In order to measure the index R_(MAX), it is necessary to to process thedata in accordance with simulation curves representing a time change ofresults of the operation or processing in at least two or more blocks byusing the method of the least squares, to evaluate coefficients K ofspecific dye as to respective blocks on the basis of the functions, asshown in FIG. 22.

Then, at a step SP51, the CPU 34 determines the constants A₁ and B₁ in ablock between times T₁ to T₂, similarly to the above embodiment. At astep SP57, the CPU 34 evaluates K₁ from K₁ =B₁ while evaluating acorrelation coefficient r_(g1), to store the same in the storage areasas 8k1 and 8k2 of the RAM 35. Similarly, the CPU 34 evaluates constantsA₂ and B₂ in a block between times T₃ and T₄ at a step SP58, andevaluates a coefficient K₂ and a correlation coefficient r_(g2) at astep SP59 to store the same in the storage areas 8k3 and 8k4. The CPU 34further determines constants A₃ and B₃ at a step SP60 and evaluates acoefficient K₃ and a correlation coefficient r_(g3) at a step SP61, tostore the same in the storage areas 8k5 and 8k6. Then the CPU 34operates determines the index R_(MAX) at a step SP62.

The times T₁ to T₆ and the coefficients K₁ to K₃ are slotted as shown inFIG. 22. The CPU 34 assumes that Cg₁, Cg₂ and Cg₃ represent valuescorresponding to specific dye concentration values at the times T₁, T₃and T₅, to display the graph as shown in FIG. 23. Referring to FIG. 23,the abscissa indicated 1/Cg and the ordinate indicated 1/K. On the basisof these data, the CPU 34 processes a and b by using the method of leastsquares, through the following operational expression:

    1/K.sub.i =a(1/C.sub.i)+b

    (i=1, 2 . . . m, m≧2, where i=1 is the first block)

Then, the CPU 34 determines the index R_(MAX) and r_(MAX) in accordancewith the following operational expression, to store the same in thestorage areas 8l1 and 8l2 of the RAM 35:

    R.sub.MAX =1/b

Although three time blocks are provided in the above embodiment, anynumber of such time blocks may be used provided at least two, are usedand the accuracy is improved as the number of time blocks is increased.

Although 1/Cg₁, 1/Cg₂ and 1/Cg₃ are plotted along the abscissa, this isa simplified approach and the index R_(MAX) can be more correctlymeasured by evaluating the coefficient A₁ on the basis of the followingoperational expression to assume the coefficient A₁ as a coefficientC₀₁, and similarly evaluating coefficients C₀₂ and C₀₃ to create thedata as shown in FIG. 22. Assuming that T₁ =5 min. and the dose of ICGis D₁ mg/kg, CO₁ may correspond to D₁, D₂ may be equal to D₁ ×CO₂ /CO₁and D₃ may be equal to D₁ ×CO₁ /CO₃. D₁ may be previously set at 2mg/kg, for example, as a value specific to the apparatus, or may beinputted by input means connected to the CPU 34.

According to the present invention as hereinabove described, vitaltissue is exposed to a first light of a wavelength absorbed by specificdye dosed by injection into the blood of the vital tissue, said dye tobe taken in and removed by the liver and a second light of a wavelengthnot absorbed by the dye and first and second photoelectric conversionsignals corresponding to the first light and the second light obtainedafter passing through the vital tissue, are sampled so that thecoefficient of a regression line expression between the first and secondphotoelectric conversion signals is determined on the basis of variablecomponents in the blood included in the sampled first and secondphotoelectric conversion signals, thereby to produce a value correlatedwith a specific dye concentration in the blood on the basis of asampling signal during a prescribed period after a lapse of apredetermined time from the injection of the specific dye and thedetermined coefficient of the regression line expression. Thus, thevalue correlated with the specific dye concentration is processed toremove factors caused by a blood flow disturbance and by any vibrationof an organism for which the present tests are to be made with the aidof a sensor secured to the organism, by performing a biocalibration,thereby to more correctly test/diagnose the liver function.

Although the present invention has been described and illustrated indetail, it is clearly understood that the same is by way of illustrationand example only and is not to be taken by way of limitation, the spiritand scope of the present invention being limited only by the terms ofthe appended claims.

INDUSTRIAL APPLICABILITY

The liver function testing apparatus according to the present inventionis employed as an apparatus for testing/diagnosing the liver function byperforming a biocalibration before injecting a specific dye selectivelytaken in and removed by the liver, into the blood for removingundersirable factors and thereafter injecting the specific dye into theblood to more correctly measure the blood plasma disappearance rate andthe retention rate.

We claim:
 1. An apparatus for testing the function of a liver,comprising light source means for exposing vital tissue to a first lightof a wavelength absorbed by a specific dye injected as a dose into bloodof said vital tissue, said specific dye to be taken in and removed bythe liver, and to a second light of a wavelength not absorbed by saidspecific dye; photoelectric conversion means for outputting first andsecond photoelectric conversion signals corresponding to said firstlight and to said second light applied to said vital tissue by saidlight source means and obtained from said vital tissue as said first andsecond light has passed through said vital tissue; sampling means forsampling said first and second photoelectric conversion signals toprovide sampling signal outputs; decision means for deciding acoefficient of a regression line expression between said first andsecond photoelectric conversion signals on the basis of variablecomponents in said blood included in said first and second photoelectricconversion signals sampled by said sampling means; and arithmetic meansconnected to receive a value correlated to a specific dye concentrationin said blood on the basis of said sampling signal output of saidsampling means during a prescribed period of time from an injection of adose of said specific dye, and connected to receive said coefficient ofsaid regression line expression decided by said decision means forcalculating a liver test result based on said sampling signal outputsand on said coefficient.
 2. The liver function testing apparatus inaccordance with claim 1, wherein said sampling means includes repeatingsampling means for sampling said first and second photoelectricconversion signals a plurality of times, and wherein said means fordeciding said coefficient of said regression line expression includesmeans for obtaining constants A and B by performing a regression lineanalysis in accordance with the following processing expression:

    log CL.sub.1 =A.log CL.sub.2 +B, wherein

CL₁ and CL₂ represent average values of said first and secondphotoelectric conversion signals repeatedly sampled by said repeatingsampling means.
 3. The liver function testing apparatus in accordancewith claim 2, wherein said arithmetic means includes means for dataprocessing including data, wherein L₁ and L₂ represent values sampledfrom said first and second photoelectric conversion signals, a value Cgcorrelated with said specific dye concentration on the basis of saidconstants A and B obtained by said obtaining means and the maximum valueL₁₀ in accordance with the following processing expression: ##EQU4## 4.The liver function testing apparatus in accordance with claim 1, furtherincluding coefficient calculating means for obtaining a coefficient of asimulation function as a function of time by using the method of leastsquares on the basis of said value correlated with said specific dyeconcentration processed by said arithmetic means.
 5. The liver functiontesting apparatus in accordance with claim 4, further including meansfor obtaining a blood plasma disappearance rate k of said specific dyeon the basis of said coefficient of said simulation function.
 6. Theliver function testing apparatus in accordance with claim 5, furtherincluding means for outputting said blood plasma disappearance rateobtained by said means for obtaining said blood plasma disappearancerate.
 7. The liver function testing apparatus in accordance with claim4, further including means for obtaining a retention rate R % of saidspecific dye in said prescribed period of time (T) on the basis of saidcoefficient of said simulation function.
 8. The liver function testingapparatus in accordance with claim 7, further including means foroutputting said retention rate.
 9. The liver function testing apparatusin accordance with claim 7, wherein said means for obtaining includesmeans for calculating said retention rate R % based on the followingexpression:

    R %=e.sup.BT,

wherein e is the base of natural logarithms, B is a constant, and T istime.
 10. The liver function testing apparatus in accordance with claim5, wherein said means for obtaining includes means for calculating, saidblood plasma disapearance rate k based on the following expression:

    k=-B, wherein

B is a constant.
 11. The liver function testing apparatus in accordancewith claim 4, further including means for calculating an index R_(MAX)expressing a total amount of a hepatic cell function.
 12. The liverfunction testing apparatus in accordance with claim 11, wherein saidmeans for calculating said index R_(MAX) includes means for injectingsaid specific dye, and computer means for dividing a prescribed timeinterval from a uniform distribution of said specific dye in said blood,into a plurality of blocks to obtain coefficients A_(i) and B_(i) on thebasis of simulation functions Cg=A_(i) e^(B) i^(t), wherein i=1, 2, . .. , m, m≧2, wherein i=1 is a first block, in respective ones of saidblocks, computer means for calculating values of Cg at initial times ofrespective ones of said blocks as C_(i) based on the assumption thatcoefficients K_(i) =-B_(i), and computer means for performing aregression line analysis on the basis of said coefficients K_(i) andvalues of C_(i) based on an expression of (1/K_(i))=a(1/C_(i))+b toobtain coefficients a and b and to determine said index as R_(MAX) =1/b.13. The liver function testing apparatus in accordance with claim 11,wherein said means for obtaining said index R_(MAX) includes means forinjecting said specific dye, computer means for dividing a prescribedtime interval from a uniform distribution of said specific dye in saidblood into a plurality of blocks to obtain coefficients A_(i) and B_(i)on the basis of simulation functions of Cg=A_(i) e^(B) i^(t), whereini=1, 2, . . . , m, m=2, where i=1 is a first block, in respective onesof said blocks, computer means for calculating a load quantity D_(i) onthe basis of said coefficients A_(i) and on the basis of a load quantityD₁ of said specific dye, whereby D_(i) is defined by the expressionD_(i) =D₁ ×A_(i) /A₁ and K_(i) =-B_(i), and computer means forperforming a regression line analysis based on the following expressionof (1/K_(i))=C(1/D_(i))+d wherein K_(i) and D_(i) are defined as setforth above to obtain coefficients C and d, thereby to obtain said indexR_(MAX) from R_(MAX) =1/d.
 14. The liver function testing apparatus inaccordance with claim 4, wherein said coefficient calculating meansincludes means for determining said constants A and B on the basis ofthe following operation expression:

    Cg=Ae.sup.Bt, wherein

t represents said prescribed period of time after injection of saidspecific dye.
 15. The liver function testing apparatus in accordancewith claim 4, whereinsaid coefficient calculating means includes meansfor determining correlation coefficient of said simulation function. 16.The liver function testing apparatus in accordance with claim 15,further including informing means for giving an alarm when saidcorrelation coefficient of said simulation function is greater than apredetermined value.
 17. The liver function testing apparatus inaccordance with claim 1, whereinsaid decision means includes computermeans for calculating a correlation coefficient of said regression lineexpression.
 18. The liver function testing apparatus in accordance withclaim 17, further including informing means for giving an alarm whensaid correlation coefficient is greater than a predetermined value. 19.The liver function testing apparatus in accordance with claim 1, furtherincluding mode selection means for selecting a biocalibration mode fordeciding said coefficient of said regression line expression by saiddecision means, and a measurement mode for for measuring said valuecorrelated with said specific dye concentration by said arithmerticmeans.
 20. The liver function testing apparatus in accordance with claim19, further including means for activating said decision means inresponse to a selection of said biocalibration mode by said modeselection means.
 21. The liver function testing apparatus in accordancewith claim 19, further including means for activating said arithmeticmeans in response to a selection of said measurement mode by said modeselection means.
 22. The liver function testing apparatus in accordancewith claim 1, further including means for setting intensity levels ofsaid first light and of said second light emitted by said light sourcemeans so that respective levels of said first and second photoelectricconversion signals are within a predetermined range.
 23. A method fortesting the function of a liver, comprising the steps of exposing vitaltissue to a first light of a wavelength absorbed by a specific dyeinjected into blood of said vital tissue said specific dye to be takenin and removed by the liver, and to a second light of a wavelength notabsorbed by said dye; sampling photoelectric conversion signalscorresponding to said first light and to said second light applied tosaid vital tissue and obtained from said vital tissue in abiocalibration mode as said first and second light has passed throughsaid vital tissue; deciding a coefficient of a regression lineexpression between said first and second photoelectric conversionsignals on the basis of variable components in said blood included inrespective sampling outputs obtained in said biocalibration mode;injecting said specific dye into said blood and thereafter sampling saidfirst and second photoelectric conversion signals during a prescribedperiod of time in a measurement mode; and calculating a value correlatedwith a specific dye concentration in said blood on the basis ofrespective sampling outputs and on the basis of said coefficient of saidregression line expression in said measurement mode for providing acalculated liver test result based on said sampling outputs and on saidcoefficient.
 24. The liver function testing method in accordance withclaim 23, further including the step of obtaining a coefficient of asimulation function as a function of time by using the method of leastsquares on the basis of said value correlated with said specific dyeconcentration.
 25. The liver function testing method in accordance withclaim 24, further including the step of calculating a blood plasmadisappearance rate of said specific dye on the basis of said coefficientof said simulation function.
 26. The liver function testing method inaccordance with claim 24, further including the step of calculating aretention rate of said specific dye in said prescribed period of time onthe basis of said coefficient of said simulation function.
 27. The liverfunction testing method in accordance with claim 24, further includingthe step of calculating an index expressing the total amount of hepaticcell function on the basis of said obtained coefficient of saidsimulation function.
 28. The liver function testing method in accordancewith claim 27, wherein said step of calculating said index expressingsaid total amount of hepatic cell function includes the step ofinjecting said specific dye, dividing a prescribed time intervalstarting from a uniform distribution of said specific dye in said blood,into a plurality of blocks to obtain coefficients A_(i) and B_(i) on thebasis of said simulation functions of Cg=A_(i) e^(B) i^(t), wherein,i=1, 2, . . . , m, m≧2, where i=1 is a first block, in respective onesof said blocks for determining values of Cg at initial times inrespective ones of said blocks as C_(i) assuming that k_(i) =-B_(i), andperforming a regression line analysis on the basis of said coefficientsK_(i) and C_(i) by using an expression of (1/K_(i))=a(1/C_(i) +b toobtain coefficients a and b for expressing said total amount of saidhepatic cell function as R_(MAX) =1/b.
 29. The liver function testingmethod in accordance with claim 27, wherein said step of calculatingsaid index expressing said total amount of said hepatic cell functionincludes the step of injecting said specific dye, dividing a prescribedtime interval starting from a uniform distribution of said specific dyein said blood, into a plurality of blocks to obtain coefficients A_(i)and B_(i) on the basis of said simulation functions of Cg=A_(i) e^(B)i^(t), wherein i=1, 2, . . . , m, m≧2, where i=1 is a first block, inrespective ones of said blocks and for determining, on the basis of saidcoefficients A_(i) and a load quantity D₁ of said specific dye, D_(i)from an expression of D_(i) =D₁.A_(i) /A₁ assuming that K_(i) =-B_(i),and performing a regression line analysis on the basis of K_(i) and D₁by using an operation expression of (1/K_(i))=C(1/D_(i)) to obtaincoefficients C and d, thereby to obtain said index R_(MAX).
 30. Theliver function testing method in accordance with claim 23, wherein saidsampling includes the step of sampling said first and secondphotoelectric conversion signals a plurality of times, performing aregression line analysis for obtaining constants A and B based on anassumption that CL₁ and CL₂ represent average values of said first andsecond photoelectric conversion signals sampled said plurality of times,and in accordance with the following regression line expression:

    logCL.sub.1 =A. log CL.sub.2 +B, and

assuming for said deciding of said coefficient of said regression lineexpression that L₁₀ represents the maximum sampled value of said firstphotoelectric conversion signal.
 31. The liver function testing methodin accordance with claim 30, further including the step of calculating,a value Cg correlated with said specific dye concentration based on thefollowing expression: ##EQU5## wherein A and B are constants, L₁₀ is themaximum value, and L₁ and L₂ represent sampled values of said first andsecond photoelectric conversion signals.
 32. A liver function testingapparatus for testing liver function, comprising light source means forexposing vital tissue to a first light of a wavelength absorbed by aspecific dye injected as a dose into blood of said vital tissue, saiddye to be taken in and removed by the liver and second light of awavelength not absorbed by said specific dye; photoelectric conversionmeans for outputting first and second photoelectric conversion signalscorresponding to said first light and said second light applied to saidvital tissue by said light source means and obtained from said vitaltissue; sampling means for sampling said first and second photoelectricconversion signals during a prescribed period after a lapse of apredetermined time from an injection of said specific dye; arithmeticmeans for calculating a correlation coefficient correlated with aspecific dye concentration in said blood on the basis of sampling valuessampled by said sampling means; and informing means for giving an alarmwhen said correlation coefficient correlated with a specific dyeconcentration is greater than a predetermined value.